US6479496B1 - Methods for treating angina with ranolazine - Google Patents

Methods for treating angina with ranolazine Download PDF

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US6479496B1
US6479496B1 US09/520,932 US52093200A US6479496B1 US 6479496 B1 US6479496 B1 US 6479496B1 US 52093200 A US52093200 A US 52093200A US 6479496 B1 US6479496 B1 US 6479496B1
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ranolazine
plasma
formulation
exercise
dose
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Andrew A. Wolff
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Gilead Sciences Inc
Gilead Palo Alto Inc
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CV Therapeutics Inc
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Priority claimed from US09/321,522 external-priority patent/US6303607B1/en
Priority to US09/520,932 priority Critical patent/US6479496B1/en
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Assigned to CV THERAPEUTICS, INC. reassignment CV THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WOLFF, ANDREW A.
Priority to PL01357273A priority patent/PL357273A1/xx
Priority to MXPA02008654A priority patent/MXPA02008654A/es
Priority to CNB018061850A priority patent/CN1323664C/zh
Priority to RU2002126615/14A priority patent/RU2002126615A/ru
Priority to AU4009201A priority patent/AU4009201A/xx
Priority to CA002402222A priority patent/CA2402222C/en
Priority to CZ20022996A priority patent/CZ20022996A3/cs
Priority to HU0204409A priority patent/HUP0204409A3/hu
Priority to JP2001564746A priority patent/JP4108980B2/ja
Priority to AU2001240092A priority patent/AU2001240092B8/en
Priority to NZ521292A priority patent/NZ521292A/en
Priority to IL15157501A priority patent/IL151575A0/xx
Priority to PCT/US2001/007287 priority patent/WO2001066093A2/en
Priority to BR0109091-7A priority patent/BR0109091A/pt
Priority to EP01914738A priority patent/EP1263439A2/en
Priority to NO20024270A priority patent/NO20024270L/no
Priority to US10/254,707 priority patent/US6562826B1/en
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Priority to US10/382,266 priority patent/US6852724B2/en
Priority to HK04100863A priority patent/HK1058003A1/xx
Priority to US11/031,220 priority patent/US20050153982A1/en
Priority to JP2007243731A priority patent/JP2008069159A/ja
Assigned to ROCHE PALO ALTO LLC reassignment ROCHE PALO ALTO LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SYNTEX (U.S.A.) INC.
Assigned to SYNTEX (U.S.A.) INC. reassignment SYNTEX (U.S.A.) INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WOLFF, ANDREW A.
Priority to AU2008212005A priority patent/AU2008212005A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROCHE PALO ALTO LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to a method for using an orally administered sustained release ranolazine dosage formulations to maintain human ranolazine plasma levels at therapeutic levels.
  • U.S. Pat. No. 5,506,229 which is incorporated herein by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissues experiencing a physical or chemical insult, including cardioplegia, hypoxic or reperfusion injury to cardiac or skeletal muscle or brain tissue, and for use in transplants.
  • Conventional oral and parenteral formulations are disclosed, including controlled release formulations.
  • Example 7D of U.S. Pat. No. 5,506,229 describes a controlled release formulation in capsule form comprising microspheres of ranolazine and microcrystalline cellulose coated with release controlling polymers.
  • ranolazine and its pharmaceutically acceptable salts and esters is oral.
  • a typical oral dosage form is a compressed tablet, a hard gelatin capsule filled with a powder mix or granulate, or a soft gelatin capsule (softgel) filled with a solution or suspension.
  • U.S. Pat. No. 5,472,707 discloses a high-dose oral formulation employing supercooled liquid ranolazine as a fill solution for a hard gelatin capsule or softgel.
  • ranolazine As set forth in application Example 3, the initial trials of ranolazine on humans suffering from angina were failures. The trials used an immediate release of ranolazine formulation at a dose level of 120 mg taken three times daily. Based upon the initial experiments, it was uncertain whether or not ranolazine could be given to humans in an amount and mode that is effective against angina.
  • ranolazine and its pharmaceutically acceptable salts are not ideally suited to ranolazine and its pharmaceutically acceptable salts, because the solubility of ranolazine is relatively high at the low pH that occurs in the stomach. Furthermore ranolazine also has a relatively short plasma half-life. The high acid solubility property of ranolazine results in rapid drug absorption and clearance, causing large and undesirable fluctuations in plasma concentration of ranolazine and a short duration of action, thus necessitating frequent oral administration for adequate treatment.
  • ranolazine in an oral dosage form once or twice daily that provides therapeutically effective plasma concentrations of ranolazine for the treatment of angina in humans.
  • this invention is a sustained release ranolazine formulation where the majority of the formulation consists of active ranolazine.
  • this invention is a method of treating a human patient who is suffering from angina or other coronary disorders by administering a sustained release ranolazine formulation to the patient once or twice daily.
  • this invention is a method for treating a mammal having a disease state for which the administration of ranolazine is indicated, comprising the once or twice-daily administration of sustained release ranolazine formulation of this invention in a manner that maintains plasma ranolazine close to minimal effective levels without peak fluctuations.
  • Still another aspect of this invention is a method of maintaining useful levels of ranolazine in human plasma by administering a ranolazine containing dosage form only one or twice daily.
  • This invention includes methods for treating a human patient suffering from a cardiovascular disease selected from arrhythmias, variant and exercise-induced angina, and myocardial infarction.
  • the method includes administering a sustained release pharmaceutical dosage form including at least 50% by weight ranolazine in no more than two tablets per dose to the human patient to maintain ranolazine plasma levels in the human patient of at least 850 ng base/mL for at least 24 hours wherein the dose is administered at a frequency selected from once, twice and three times over 24 hours.
  • FIG. 1 is a plot of symptom limited exercise duration of human patients treated with a placebo or various amounts of ranolazine in sustained formulation bid as reported in Example 9;
  • FIG. 2 is a plot of exercise time to angina for human patients administered a placebo or various amounts of ranolazine in a sustained release dosage formulation bid as reported in Example 9;
  • “Ranolazine” is the compound ( ⁇ )-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine-acetamide, or its enantiomers (R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide, and (S)-( ⁇ )N-2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide and their pharmaceutically acceptable salts, and mixtures thereof.
  • ranolazine plasma concentrations used in the specification and examples refers to ranolazine free base.
  • “Optional” and “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optional pharmaceutical excipients” indicates that a formulation so described may or may not include pharmaceutical excipients other than those specifically stated to be present, and that the formulation so described includes instances in which the optional excipients are present and instances in which they are not.
  • Treating” and “treatment” refer to any treatment of a disease in a mammal, particularly a human, and include:
  • sustained release refers to formulations or dosage units of this invention that are slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of about six hours or more.
  • Preferred sustained release formulations are those exhibiting plasma concentrations of ranolazine suitable for no more than twice daily administration with two or less tablets per dosing as described below.
  • Plasma ranolazine concentration is a mean concentration determined by analyzing the concentration of ranolazine in as few as five to as many as ten humans who are on the same dosing schedule. It is important that the ranolazine concentration is a mean value because of variances in ranolazine concentrations in individuals that may be caused by differences in weight, metabolism, or disease states which may cause one person to metabolize ranolazine faster or slower than an average person.
  • the plasma ranolazine levels are determined from drawn blood onto heparin.
  • C trough residual concentration at 8 hours post-dose for IR formulations and 12 hours post-dose for SR formulations A-C of Example 2.
  • AUC x area under the curve after x hours or time interval
  • This invention involves sustained release ranolazine dosage forms as well as methods for administering sustained release ranolazine dosage forms of this invention to provide for therapeutic plasma levels of ranolazine.
  • the sustained release ranolazine formulations of this invention are preferably in the form of a compressed tablet comprising an intimate mixture of ranolazine and a partially neutralized pH-dependent binder that controls the rate of ranolazine dissolution in aqueous media across the range of pH in the stomach (typically approximately 2) and in the intestine (typically approximately about 5.5).
  • one or more pH-dependent binders are chosen to control the dissolution profile of the ranolazine formulation so that the formulation releases ranolazine slowly and continuously as the formulation passed through the stomach and gastrointestinal tract.
  • the dissolution control capacity of the pH-dependent binder(s) is particularly important in a sustained release ranolazine formulation because a sustained release formulation that contains sufficient ranolazine for twice daily administration may cause untoward side effects if the ranolazine is released too rapidly (“dose-dumping”).
  • the pH-dependent binders suitable for use in this invention are those which inhibit rapid release of drug from a tablet during its residence in the stomach (where the pH is—below about 4.5), and which promotes the release of a therapeutic amount of ranolazine from the dosage form in the lower gastrointestinal tract (where the pH is generally greater than about 4.5).
  • enteric binders and coating agents have the desired pH dissolution properties.
  • phthalic acid derivatives such as the phthalic acid derivatives of vinyl polymers and copolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates, hydroxyalkylcellulose acetates, cellulose ethers, alkylcellulose acetates, and the partial esters thereof, and polymers and copolymers of lower alkyl acrylic acids and lower alkyl acrylates, and the partial esters thereof.
  • Preferred pH-dependent binder materials which can be used in conjunction with ranolazine to create a sustained release formulation are methacrylic acid copolymers.
  • Methacrylic acid copolymers are copolymers of methacrylic acid with neutral acrylate or methacrylate esters such as ethyl acrylate or methyl methacrylate.
  • a most preferred copolymer is methacrylic acid copolymer, Type C, USP (which is a copolymer of methacrylic acid and ethyl acrylate having between 46.0% and 50.6% methacrylic acid units).
  • Such a copolymer is commercially available, from Röhm Pharma as Eudragit® L 100-55 (as a powder) or L30D-55 (as a 30% dispersion in water).
  • Other pH-dependent binder materials which may be used alone or in combination in a sustained release ranolazine dosage form include hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate, and the like.
  • One or more pH-dependent binders are present in the ranolazine dosage forms of this invention in an amount ranging from about 1 to about 20 wt %, more preferably from about 5 to about 12 wt % and most preferably about 10 wt %.
  • pH-independent binders may be in used in sustained release ranolazine oral dosage forms. It is to be noted that pH-dependent binders and viscosity enhancing agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like, do not themselves provide the required dissolution control provided by the identified pH-dependent binders.
  • the pH-independent binders are present in the formulation of this invention in an amount ranging from about 1 to about 10 wt %, and preferably in amount ranging from about 1 to about 3 wt % and most preferably about 2.0 wt %.
  • ranolazine is relatively insoluble in aqueous solutions having a pH above about 6.5, while the solubility begins to increase dramatically below about pH 6.
  • Increasing the pH-dependent binder content in the formulation decreases the release rate of ranolazine from the formulation at pH is below 4.5 typical of the pH found in the stomach.
  • the enteric coating formed by the binder is less soluble and increases the relative release rate above pH 4.5, where the solubility of ranolazine is lower.
  • a proper selection of the pH-dependent binder allows for a quicker release rate of ranolazine from the formulation above pH 4.5, while greatly affecting the release rate at low pH.
  • Partial neutralization of the binder facilitates the conversion of the binder into a latex like film which forms around the individual ranolazine granules. Accordingly, the type and the quantity of the pH-dependent binder and amount of the partial neutralization composition are chosen to closely control the rate of dissolution of the ranolazine from the formulation.
  • the sustained release formulation may also contain pharmaceutical excipients intimately admixed with the ranolazine and the pH-dependent binder.
  • Pharmaceutically acceptable excipients may include, for example, pH-independent binders or film-forming agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. the methyl methacrylate/ethyl acrylate copolymers sold under the trademark Eudragit® NE by Röhm Pharmal, starch, gelatin, sugars, carboxymethylcellulose, and the like.
  • diluents such as lactose, mannitol, dry starch, microcrystalline cellulose and the like; surface active agents such as polyoxyethylene sorbitan esters, sorbitan esters and the like; and coloring agents and flavoring agents.
  • Lubricants such as talc and magnesium stearate
  • other tableting aids are also optionally present.
  • the sustained release ranolazine formulations of this invention have a ranolazine content of above about 50% by weight to about 95% or more by weight, more preferably between about 70% to about 90% by weight and most preferably from about 70 to about 80% by weight; a pH-dependent binder content of between 5% and 40%, preferably between 5% and 25%, and more preferably between 5% and 15%; with the remainder of the dosage form comprising pH-independent binders, fillers, and other optional excipients.
  • sustained release ranolazine formulations of this invention consist, essentially of:
  • ranolazine and pH-dependent binder and any optional excipients are intimately mixed (dry-blended).
  • the dry-blended mixture is then granulated in the presence of an aqueous solution of a strong base which is sprayed into the blended powder.
  • the granulate is dried, screened, mixed with optional lubricants (such as talc or magnesium stearate), and compressed into tablets.
  • Preferred aqueous solutions of strong bases are solutions of alkali metal hydroxides, such as sodium or potassium hydroxide, preferably sodium hydroxide, in water (optionally containing up to 25% of water-miscible solvents such as lower alcohols).
  • the resulting ranolazine containing tablets may be coated with an optional film-forming agent, for identification, taste-masking purposes and to improve ease of swallowing.
  • the film forming agent will typically be present in an amount ranging from between 2% and 4% of the tablet weight.
  • Suitable film-forming agents are well-known to the art and include hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate/methyl-butyl methacrylate copolymers ⁇ Eudragit® E—Röhm Pharma), and the like. These film-forming agents may optionally contain colorants, plasticizers, and other supplemental ingredients.
  • the compressed tablets preferably have a hardness sufficient to withstand 8 Kp compression.
  • the tablet size will depend primarily upon the amount of ranolazine in the tablet.
  • the tablets will include from 300 to 1100 mg of ranolazine free base.
  • the tablets will include amounts of ranolazine free base ranging from 400-600 mg, 650-850 mg, and 900-1100 mg.
  • the time during which the ranolazine containing powder is wet mixed is controlled.
  • the total powder mix time i.e. the time during which the powder is exposed to sodium hydroxide solution, will range from 1 to 10 minutes and preferably from 2 to 5 minutes.
  • the particles are removed from the granulator and placed in a fluid bed dryer for drying at about 60° C.
  • ranolazine formulations that provide lower peak plasma ranolazine levels and yet effective plasma concentrations of ranolazine for up to 12 hours and more after administration, when the ranolazine used as its free base, rather than as the more pharmaceutically common ranolazine dihydrochloride salt or as another salt or ester.
  • ranolazine free base affords at least one advantage: The proportion of ranolazine in the tablet can be increased, since the molecular weight of ranolazine free base is only 85% that of ranolazine dihydrochloride. In this manner, delivery of an effective amount of ranolazine is achieved while limiting the physical size of the dosage unit.
  • sustained release ranolazine formulations of this invention are prepared by a process that essentially involves only water as a solvent, and utilizes standard pharmaceutical processing techniques and equipment.
  • the oral sustained release ranolazine dosage formulations of this invention are administered one, twice; or three times in a 24 hour period in order to maintain a plasma ranolazine level above the threshold therapeutic level and below the maximally tolerated levels, of between about 550 and 7500 ng base/mL in a patient. This corresponds to an amount of ranolazine 2 HCl ranging from about 644 ng/mL to about 8782 ng/mL.
  • the timing of the oral ingestion of the ranolazine oral dosage forms should be controlled to insure that the plasma ranolazine level does not exceed about 7500 ng base/mL and preferably so that the plasma ranolazine level does not exceed about 5000 ng base/mL an most preferably so that is does not exceed 3800 ng base/mL. In some instances it may be beneficial to limit the peak plasma ranolazine level to no more than about ng base/mL At the same time, the plasma trough ranolazine levels should preferably not fall below about 1000 ng base/mL, and in some instances should not fall below 1700 ng base/mL.
  • the oral ranolazine dosage forms described herein are administered once or twice daily. If the dosage forms are administered twice daily, then it is preferred that the oral ranolazine dosage forms are administered at about twelve hour intervals.
  • the plasma ranolazine levels are typically achieved at from about 30 minutes to eight hours or more after initially ingesting the dosage form while trough plasma ranolazine levels are achieve at about the time of ingestion of the next scheduled dosage form.
  • the sustained release ranolazine formulations of this invention provide the therapeutic advantage of minimizing variations in ranolazine plasma concentration while permitting, at most, twice-daily administration.
  • the formulation may be administered alone, or (at least initially) in combination with an immediate release formulation if rapid achievement of a therapeutically effective plasma concentration of ranolazine is desired or by soluble IV formulations and oral dosage forms.
  • This Example describes a method of preparing immediate release (IR) ranolazine formulations.
  • Ranolazine dihydrochloride (4000 g), microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g), and croscarmellose sodium (100 g) powders were intimately mixed together in a Fielder PMA 65 mixer-granulator, and sufficient water was then added, with mixing to form a granulate.
  • the granulate was dried in an Aeromatic Strea-5 fluid bed drier, screened, and mixed with magnesium stearate (100 g).
  • the mixture was filled into hard gelatin capsules to a fill weight of, for example, 500 mg per capsule to achieve a dose of 400 mg of ranolazine dihydrochloride (equivalent to 342 mg of ranolazine free base) per capsule, but may be filled to fill weight of 30 to 400 mg of ranolazine dihydrochloride.
  • This Example describes a method of preparing sustained release (SR) ranolazine formulations.
  • SR Formulation A sustained release formulation, designated as SR Formulation A, and including pH-dependent and pH-independent binders was prepared by combining Ranolazine (2500 g), methacrylic acid copolymer, Type C (Eudragit® L 100-55—Röhm Pharma) (1000 g), microcrystalline cellulose (Avicel®) (100 g) (710 g), and polyvinyl pyrrolidinone powders were intimately mixed together in a Fielder PMA 65 mixer-granulator.
  • the mixture was granulated with a solution of sodium hydroxide (40 g) in water, and a 30% aqueous dispersion of methyl methacrylate/ethyl acrylate copolymer (Eudragit® NE 30 D—Röhm Pharma) (1667 g) was added to the wet mass.
  • the resulting granulate was dried in an Aeromatic Strea-5 fluid bed drier, screened, and then mixed with croscarmellose sodium (100 g) and magnesium stearate (50 g).
  • the mixture was compressed into 684 mg tablets with a Manesty B tablet press to achieve dose of 342 mg of ranolazine free base per tablet. This formulation is referred to as SR Formulation A.
  • SR Formulation B was prepared in the same manner as SR Formulation A except that the Eudragit® L 100-55 was reduced to 500 g, and the Eudragit® NE 30 D was replaced by a 40% aqueous dispersion of a methyl methacrylate/ethyl acrylate copolymer (Eudragit® NE 40 D—Röhm Pharma) (2500 g).
  • the resulting (SR) formulation included 342 mg ranolazine free base per tablet.
  • ranolazine free base (342 mgs) was blended with microcrystalline cellulose and polyvinyl pyrrolininone K25, granulated with water, dried, and blended with croscarmellose sodium and magnesium stearate. The blend was compressed into tablets and coated with an enteric coating.
  • SR Formulation D including a pH dependent binder and a pH independent binder was prepared by combining Ranolazine (7500 g), Eudragit® L 100-55 (1000 g), hydroxypropyl methylcellulose (Methocel® E5—source) (200 g), and microcrystalline cellulose (Avicel®) (1060 g) by intimate mixing.
  • the mixed powders were granulated with a solution of sodium hydroxide (40 g) in water (1900 to 2500 grams).
  • the granulate was dried and screened, mixed with magnesium stearate (200 g), and compressed for example into tablets weighing 667 mg to achieve a dose of 500 mg of ranolazine free base per tablet.
  • the tablets were spray coated in a 24 inch Accelacota® cylindrical pan coater with OPADRY film coating solution to a 2-4% weight gain.
  • OPADRY film coating solutions are available in a variety of colors from Colorcon, West Point, Pa.
  • the mean peak plasma concentrations of ranolazine free base at 1 hour after dose were 94, 219 and 510 ng/mL, respectively, and the mean trough plasma concentrations at 8 hours after dose were 18, 37 and 90 ng/mL, respectively.
  • Example 2 the safety and anti-ischemic effects of high plasma ranolazine levels in a large group of angina patients was evaluated and the duration of any effects during steady-state dosing with bid and tid regimens was assessed.
  • patients with chronic stable angina pectoris who were responsive to conventional antianginal drugs were treated with 3 ranolazine .2HCl dosing regimens: 267 mg tid, 400 mg bid and 400 mg tid IR Formulations of Example 1.
  • Exercise testing parameters and ranolazine free base concentrations were determined at peak and trough plasma levels.
  • exclusion criteria included unstable angina or myocardial infarction within the preceding 3 months, heart failure defined as New York Heart Association Class III or IV, significant valvular or congenital heart disease that was uncorrected, need for digoxin or long-acting nitrate therapy, labile diabetes mellitus, or other serious conditions that would confuse follow-up evaluation.
  • ranolazine .2HCl dosing regimens (267 mg tid, 400 mg bid, 400 mg tid) and a placebo were administered during the treatment phase.
  • Patients took one capsule containing either 267 mg or 400 mg of ranolazine dihydrochloride, or placebo at 8:00 a.m., 4:00 p.m., 8:00 p.m. and 12:00 a.m. All capsules were identical in appearance.
  • Patients were randomized to 1 of 4 treatment sequences, with 25% of the patients assigned to each sequence. Each treatment was administered for 1 week, with one treatment repeated during a fifth 1-week period.
  • ETT-1 screening exercise treadmill test
  • ETT-2 Sheffield modified Bruce protocol
  • ETT-2 Long-acting nitrates were always withdrawn first; beta-blockers; and calcium antagonists could be withdrawn in either order from patients not receiving long-acting nitrates.
  • ETT-3 a second qualifying ETT was performed in which the time to onset angina had to be within ⁇ 15% of that observed during ETT-2.
  • each of the qualifying ETTs had to have ECG signs of ischemia ( ⁇ 1 mm horizontal or down-sloping ST-segment depression in 3 consecutive beats). Patients meeting these criteria were used in the study.
  • Blood pressure (by cuff) and heart rate were monitored before all ETTs, during the ETT, during the last minute of each stage of the test, at onset angina, at the point of maximum exercise, and during recovery (every minute for 4 minutes, then every 5 minutes until values returned to baseline). Heart rates also was monitored continuously and standard 12-lead ECG recordings were done immediately before exercise with the patient standing on the treadmill, at the end of each stage of exercise, at the maximally tolerated exercise load, and at the termination of exercise.
  • Exercise test parameters improved at peak ranolazine concentrations (ranolazine-placebo) whether or not patients were receiving beta-blockers. These improvements were slightly larger in magnitude in the 205 patients not receiving beta-blockers compared to the 107 patients who received beta-blockers. But the differences between those receiving beta-blockers and those not receiving them did not achieve statistical significance for any exercise parameter. In patients not receiving beta-blockers, all exercise parameters improved significantly on each of the 3 ranolazine regimens, and also with all ranolazine regimens combined. Similar trends were observed in the smaller number of patients receiving beta-blockers. Analyses of exercise data from patients taking calcium antagonists compared with those not receiving calcium antagonists produced similar findings.
  • Table 3 summarizes the mean peak and trough plasma ranolazine concentrations, in terms of ranolazine dihydrochloride base, for all patients by gender and for each dosing regimen.
  • the plasma mean peak concentrations ranged from 1346 to 2128 ng per mL ranolazine free base.
  • the 400 mg tid dosing regimen was associated with the highest ranolazine plasma concentrations.
  • Mean trough ranolazine plasma concentrations ranged from 235 to 514 ng per mL.
  • Mean peak ranolazine plasma concentrations were somewhat higher in females than in males, but there were no sex differences in plasma concentrations evident in trough.
  • ranolazine is an effective antianginal and anti-ischemic compound in patients with chronic stable angina pectoris.
  • the three ranolazine dosing regimens used prolonged time to onset of angina and duration of exercise as well as time to 1-mm ST-segment depression on average about 0.33 minutes over that observed with placebo. Improvement in exercise parameters was observed in the present study not only in patients receiving concomitant antianginal therapy (eg, beta-blockers and calcium antagonists), but also in the subgroup who received only ranolazine monotherapy. In the latter patients, the treatment effect appeared to be somewhat greater in magnitude. This suggests that ranolazine also may be useful in monotherapy in patients with chronic stable angina pectoris.
  • Ranolazine improves exercise parameters with no detectable effect on heart rate and blood pressure in patients with chronic stable angina pectoris. It is likely that a threshold ranolazine plasma concentration above about 550 ng per mL must be obtained to detect these antianginal and anti-ischemic effects. Ranolazine is well tolerated over a wide range of plasma concentrations. Further study using larger doses of a sustained release preparation are warranted to fully evaluate this novel metabolic concept for management of ischemia.
  • Example 2D This Example details a single-ascending dose, crossover-design study that assessed the safety and pharmacokinetic profile of single oral dose of ranolazine base SR Formulation of Example 2D.
  • Human subjects were divided into three groups. Group 1 received 500, 750 and 1000 mg ranolazine SR. Group 2 received 1250 and 1750 mg ranolazine SR. Group 3 received 1500 and 2000 mg ranolazine SR. Each group also had a randomized placebo phase.
  • Mean pharmacokinetic parameters following single oral doses of the ranolazine SR does are detailed in Table 6 below:
  • ranolazine was slowly released from the SR formulation, and consequently the pharmacokinetics were dissolution-rate limited. This resulted in extended plasma drug concentration-time profiles at all dose levels, with peak plasma levels observed at 2 to 4 hours post dose.
  • Example 2D evaluated the safety and tolerability of administering racemic ranolazine free base formulations as in Example 2D.
  • Steady state was tested for in each dose level, using C 48h , C 72h and C 96h and log transformed data, by analysis of covariance and by testing whether the coefficient for time was significantly different (defined as p ⁇ 0.05) from 0. These tests were made using two-sided t-tests with estimates of variability from the ANOVA models. Steady state was also assessed by comparing means for C 48h , C 72h and C 96h using a mixed effects ANOVA model and untransformed and log, transformed data. For hemodynamic parameters, Day 1 pre-dose treatment means and Day 5 data were compared across treatments via two-sided t-tests using estimates of variability from mixed effects ANOVA models. Ninety and 95% confidence intervals were calculated for the treatment comparisons. No adjustments were made for multiple comparisons.
  • MARISA is the first study of sustained release ranolazine (SR) in stable angina.

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US09/520,932 US6479496B1 (en) 1998-09-10 2000-03-08 Methods for treating angina with ranolazine
EP01914738A EP1263439A2 (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
BR0109091-7A BR0109091A (pt) 2000-03-08 2001-03-07 Formulações de ranolazina de liberação sustentada
PCT/US2001/007287 WO2001066093A2 (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
IL15157501A IL151575A0 (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
RU2002126615/14A RU2002126615A (ru) 2000-03-08 2001-03-07 Рецептуры ранолазина пролонгированного действия
HU0204409A HUP0204409A3 (en) 2000-03-08 2001-03-07 Sustained release ranolazine pharmaceutical compositions
CNB018061850A CN1323664C (zh) 2000-03-08 2001-03-07 雷诺嗪缓释制剂
PL01357273A PL357273A1 (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
AU4009201A AU4009201A (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
CA002402222A CA2402222C (en) 2000-03-08 2001-03-07 Sustained release ranolazine formulations
CZ20022996A CZ20022996A3 (cs) 2000-03-08 2001-03-07 Léková forma s prodlouženým uvolňováním obsahující ranolazin pro léčení kardiovaskulárních onemocnění
MXPA02008654A MXPA02008654A (es) 2000-03-08 2001-03-07 Formulaciones de ranolazina de liberacion prolongada.
JP2001564746A JP4108980B2 (ja) 2000-03-08 2001-03-07 持続放出ラノラジン製剤
AU2001240092A AU2001240092B8 (en) 1998-09-10 2001-03-07 Sustained release ranolazine formulations
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US6562826B1 (en) * 1998-09-10 2003-05-13 Cv Therapeutics, Inc. Sustained release ranolazine formulations
US6617328B2 (en) * 1998-09-10 2003-09-09 Cv Therapeutics, Inc Sustained release ranolazine formulations
US6620814B2 (en) * 1998-09-10 2003-09-16 Cv Therapeutics, Inc. Sustained release ranolazine formulations
US20040029890A1 (en) * 1998-09-10 2004-02-12 Cv Therapeutics, Inc. Sustained release ranolazine formulations
US6852724B2 (en) * 1998-09-10 2005-02-08 Cv Therapeutics, Inc. Sustained release ranolazine formulations
US6864258B2 (en) * 1998-09-10 2005-03-08 Andrew A. Wolff Sustained release ranolazine formulations
US20050059667A1 (en) * 1998-09-10 2005-03-17 Wolff Andrew A. Sustained release ranolazine formulations
US20050153982A1 (en) * 1998-09-10 2005-07-14 Cv Therapeutics, Inc. Sustained release ranolazine formulations
US20060147521A1 (en) * 1998-09-10 2006-07-06 Wolff Andrew A Sustained release ranolazine formulations
US20030166659A1 (en) * 1998-09-10 2003-09-04 Wolff Andrew A. Sustained release ranolazine formulations
US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
WO2003099281A2 (en) 2002-05-21 2003-12-04 Cv Therapeutics, Inc. Administration of a partial fatty acid inhibitor such as ranolazine for the treatment of diabetes
US20080009503A1 (en) * 2002-05-21 2008-01-10 Andrew Wolff Method of treating diabetes
US8822473B2 (en) * 2002-05-21 2014-09-02 Gilead Sciences, Inc. Method of treating diabetes
EP2332540A1 (en) 2002-05-21 2011-06-15 Cv Therapeutics, Inc. Administration of ranolazine for the treatment of diabetes
US8883750B2 (en) 2002-05-21 2014-11-11 Gilead Sciences, Inc. Method of treating diabetes
US8314104B2 (en) 2002-05-21 2012-11-20 Gilead Sciences, Inc. Method of treating diabetes
US20100197701A1 (en) * 2002-05-21 2010-08-05 Gilead Palo Alto, Inc. Method of treating diabetes
US8313776B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8425936B2 (en) 2003-07-21 2013-04-23 Shionogi Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8758820B2 (en) 2003-08-11 2014-06-24 Shionogi Inc. Robust pellet
US8062672B2 (en) 2003-08-12 2011-11-22 Shionogi Inc. Antibiotic product, use and formulation thereof
US9144548B2 (en) 2003-08-12 2015-09-29 Shionogi Inc. Antibiotic product, use and formulation thereof
US8246996B2 (en) 2003-08-29 2012-08-21 Shionogi Inc. Antibiotic product, use and formulation thereof
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
US8715727B2 (en) 2004-07-02 2014-05-06 Shionogi Inc. Tablet for pulsed delivery
US20060177502A1 (en) * 2005-01-06 2006-08-10 Srikonda Sastry Sustained release pharmaceutical formulations
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US20080214555A1 (en) * 2007-02-13 2008-09-04 Markus Jerling Use of ranolazine for the treatment of cardiovascular diseases
US20080248112A1 (en) * 2007-02-13 2008-10-09 Brent Blackburn Use of ranolazine for the treatment of coronary microvascular diseases
US20080193530A1 (en) * 2007-02-13 2008-08-14 Brent Blackburn Use of ranolazine for the treatment of non-coronary microvascular diseases
US20090111826A1 (en) * 2007-02-13 2009-04-30 Louis Lange Use of ranolazine for the treatment of cardiovascular diseases
US20080214556A1 (en) * 2007-02-13 2008-09-04 Markus Jerling Use of ranolazine for the treatment of cardiovascular diseases
US7943620B2 (en) 2007-03-07 2011-05-17 Concert Pharmaceuticals, Inc. Anti-anginal compounds
US20080318969A1 (en) * 2007-03-07 2008-12-25 Harbeson Scott L Anti-anginal compounds
US20080233191A1 (en) * 2007-03-22 2008-09-25 Brent Blackburn Use of ranolazine for elevated brain-type natriuretic peptide
US20080299195A1 (en) * 2007-05-31 2008-12-04 Brent Blackburn Use of ranolazine for elevated brain-type natriuretic peptide
US20080312247A1 (en) * 2007-06-13 2008-12-18 Auspex Pharmaceuticals, Inc. Substituted piperazines
US20100197684A1 (en) * 2007-07-05 2010-08-05 Gilead Palo Alto, Inc. Substituted heterocyclic compounds
US8716319B2 (en) 2007-07-05 2014-05-06 Gilead Sciences, Inc. Substituted heterocyclic compounds
US20090012103A1 (en) * 2007-07-05 2009-01-08 Matthew Abelman Substituted heterocyclic compounds
US9045428B2 (en) 2007-07-05 2015-06-02 Gilead Sciences, Inc. Substituted heterocyclic compounds
US20090203707A1 (en) * 2008-02-06 2009-08-13 Sridharan Rajamani Methods for treating pain
US20100292217A1 (en) * 2009-05-14 2010-11-18 Gilead Palo Alto, Inc. Ranolazine for the treatment of cns disorders
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
WO2013043925A1 (en) 2011-09-21 2013-03-28 Gilead Sciences, Inc. Sodium channel blockers reduce glucagon secretion
WO2021126884A1 (en) 2019-12-16 2021-06-24 Tenax Therapeutics, Inc. LEVOSIMENDAN FOR TREATING PULMONARY HYPERTENSION WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION (PH-HF-pEF)

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